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Strain-induced vascular endothelial cell proliferation requires PI3K-dependent mTOR-4E-BP1 signal pathway

Wei Li1, Bauer E Sumpio

  • 1Dept. of Surgery, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520, USA.

American Journal of Physiology. Heart and Circulatory Physiology
|December 14, 2004
PubMed

Insights

Cyclic strain enhances vascular endothelial cell proliferation through the PI3K-mTOR pathway. Inhibiting this pathway with rapamycin or PI3K inhibitors reduces strain-induced cell growth and S6K activation.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Physiology

Background:

  • Vascular endothelial cells (ECs) are crucial for blood vessel function.
  • Mechanical forces like cyclic strain influence EC behavior.
  • The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway regulates cell growth and proliferation.

Purpose of the Study:

  • To investigate the role of the PI3K-dependent mTOR-eukaryotic initiation factor 4E binding protein 1 (4E-BP1) pathway and S6 kinase (S6K) in cyclic strain-induced EC proliferation.

Main Methods:

  • Bovine aortic ECs were subjected to cyclic strain (10% at 60 cycles/min for up to 24 hours).
  • Inhibitors of PI3K (wortmannin, LY-294002), mTOR (rapamycin), and MEK1 (PD-98059) were used to assess pathway involvement.
  • Cell proliferation and protein activation (S6K, extracellular signal-regulated kinases 1 and 2) were measured.

Main Results:

  • Cyclic strain significantly increased EC proliferation.
  • Rapamycin and PI3K inhibitors attenuated strain-induced EC proliferation and S6K activation.
  • PD-98059 did not affect strain-induced EC proliferation or S6K activation but inhibited ERK1/2 activation.
  • Cyclic strain activated 4E-BP1, an effect inhibited by PI3K inhibitors.

Conclusions:

  • The PI3K-dependent S6K-mTOR-4E-BP1 signaling pathway is critically involved in mediating enhanced proliferation of bovine aortic ECs under cyclic strain.
  • This pathway represents a potential therapeutic target for conditions involving altered vascular remodeling due to mechanical stress.

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